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The effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) on negative symptoms of schizophrenia and the follow-up study
Neuroscience Letters 584 (2015) 197–201
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Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
The effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) on negative symptoms of schizophrenia and the follow-up study Wen Xiang Quan a,b,1 , Xiao Lin Zhu c,1 , Hong Qiao a,b , Wu Fang Zhang a,b , Shu Ping Tan c , Dong Feng Zhou a,b , Xiang Qun Wang a,b,∗ a
Institute of Mental Health, Peking University, 51 Hua Yuan Bei Road, Beijing 100191, China Key Laboratory of Mental Health, Ministry of Health, Institute of Mental Health, The Sixth Hospital, Peking University, China c Center for Psychiatric Research, Beijing Huilongguan Hospital, Beijing 100096, China b
h i g h l i g h t s • 6-week rTMS significantly improved the negative symptoms of schizophrenia. • CGI severity of illness scale was not improved by rTMS in schizophrenia. • The improvement of negative symptoms in schizophrenia was maintained for 24 weeks.
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Article history: Received 9 July 2014 Received in revised form 25 September 2014 Accepted 16 October 2014 Available online 24 October 2014 Keywords: Repetitive transcranial magnetic stimulation Schizophrenia Negative symptoms
a b s t r a c t In this double-blind, randomized controlled study, we assessed the therapeutic effects of high-frequency left dorsolateral prefrontal cortex (DLPFC) repetitive transcranial magnetic stimulation (rTMS) on negative symptoms of schizophrenia. For the study, 117 patients with prominent negative symptoms were randomized to a 20-day course of either active rTMS applied to the left DLPFC (n = 78) or sham rTMS (n = 39). The primary outcome measures were the Positive and Negative Symptom Scale (PANSS) and the Scale for the Assessment of Negative Symptoms (SANS). Secondary outcomes included the Clinical Global Impressions Scale (CGI) and the Udvalg for Kliniske Under sogelser (UKU) Side Effect Rating Scale. We found that treatment with high-frequency rTMS for 6weeks significantly improved negative symptoms in the active group as compared to the sham group. However, active rTMS was not correlated with significant improvement in the CGI severity of illness scale (CGI-S). The improvement of negative symptoms persisted to the 24-week follow-up assessment. These results indicate that there is a lasting beneficial effect of rTMS on negative symptoms in absence of decrease in CGI scores. We conclude that rTMS may serve as a relatively noninvasive treatment that alleviates negative symptoms in patients with schizophrenia. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction The core symptoms of schizophrenia can be divided into negative and positive symptoms. Positive symptoms include abnormal emotions and behavior, such as delusions, disorganized thoughts and actions, and hallucinations. In contrast, negative symptoms are defined as an absence of normal emotions and behaviors, including apathy, loss of interest in everyday activities,
∗ Corresponding author at: Institute of Mental Health, Peking University, 51 Hua Yuan Bei Road, Beijing 100191, China. Tel.: +86 10 82802835; fax: +86 10 62026310. E-mail address: [email protected] (X.Q. Wang). 1 Quan WX and Zhu XL contributed to this work equally. http://dx.doi.org/10.1016/j.neulet.2014.10.029 0304-3940/© 2014 Elsevier Ireland Ltd. All rights reserved.
and feelings of social isolation. Negative symptoms contribute substantially to the prolonged course and mental disability associated with schizophrenia. While negative symptoms can be attenuated by atypical antipsychotics, the benefit is clinically unsatisfactory. Therefore, developing a more effective therapy for negative symptoms is critical for improving schizophrenia treatment. Studies have consistently suggested that prefrontal dysfunction, particularly in the dorsolateral prefrontal cortex (DLPFC), is involved in the pathophysiology of negative symptoms of schizophrenia [7,21,27]. Further, indices of negative symptoms have been shown to negatively correlate with blood flow to the frontal cerebrum [24] and prefrontal perfusion [17]. Structural impairments of the prefrontal cortex in schizophrenia have also
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been associated with negative symptoms and this may be a corollary of dopamine hypoactivation [15]. Repetitive transcranial magnetic stimulation (rTMS) is a neurophysiological technique introduced by Barker in 1985 [2] that permits noninvasive electromagnetic neurostimulationin specific areas of cerebral cortex. Animal and human studies have shown that rTMS modulates neuronal activity of cortical brain areas and relevant neuronal circuits, while also affecting the regulation of serotonin receptors and the release of dopamine in the mesolimbic and mesostriatal pathways [11,14,26]. Thus, rTMS represents an attractive potential therapy for schizophrenia; however, reports on the efficacy of rTMS in treating the disease are conflicting. The most important factors that influence rTMS experimental results are the stimulation parameters (e.g., the number of stimulating pulses administered, the total number of stimulation sessions, the stimulation site, the conditions for blinding, etc.). Therefore, different rTMS protocols may explain these contradictory findings, highlighting the importance of optimizing rTMS parameters. It has been demonstrated repeatedly that high-frequency rTMS (5–25 Hz) applied over the left prefrontal cortex (PFC) increases brain excitability, whereas low-frequency rTMS (1 Hz and low) has the opposite effect [8]. The first report on rTMS effects on negative symptoms was an open study targeting the prefrontal cortex of six patients with 10 days of 20 Hz rTMS at 80% MT [4] that described a general reduction of the negative symptoms subscale of the Positive and Negative Symptom Scale (PANSS). Two follow-up studies also reported improvement of negative symptoms [10,25]. However, the results of subsequent parallel design, randomized, double-blind, controlled studies with a longer testing period and larger subject group have been contradictory despite several methodological improvements (e.g., parallel design and a higher number of pulses) [6,9,11,16,20,22]. High-frequency rTMS to the left DLPFC did not alleviate negative symptoms in two studies with samples of 22 [9] and 16 [20] for chronic schizophrenia patients. In contrast, Hajak and Jin were able to show a significant improvement in total PANSS negative symptoms over time when compared to sham rTMS using a higher dosage and bilateral frontal cortex as a treatment site [6,11]. The intensity of rTMS was also higher in this study (110% vs. 90% MT) and included patients with schizoaffective disorder, who respond better to rTMS than schizophrenia patients. Prikryl reported similar results using the same parameters and an extended treatment time (3 weeks vs. 2 weeks) [22]. The discrepancies between studies may be due to different experimental paradigms, stimuli, and sample sizes. As result, no definitive conclusions regarding the treatment potential of rTMS can presently be made, and it remains necessary to demonstrate symptom reductions are sustained. Moreover, the clinical significance (i.e., degree of functional improvement) of these effects is largely unknown. In the present study, we aimed to investigate the efficacy of high-frequency rTMS on negative symptoms and general clinical state assessed by PANSS, Scale for the Assessment of Negative Symptoms (SANS), and Clinical Global Impression (CGI) scale in a relatively large and well-characterized sample of patients with schizophrenia through a randomized, double-blind, and sham-controlled trial. We hypothesized that negative symptoms and the general clinical state would be significantly improved in patients with schizophrenia following the application of high-frequency rTMS to the left dorsolateral prefrontal cortex (DLPFC).
Anding Hospital between January 2007 and June 2010. Individuals who meet DSM-IV diagnosis for schizophrenia [1] and had a PANSS negative symptom score ≥ 20 were enrolled. All diagnoses were made by a single psychiatrist and then confirmed by a senior psychiatrist. Patients were included only if they were stabilized for at least 3 months by a consistent regimen of antipsychotics. The age of enrollees ranged from 20 to 60 years. All patients were screened for normal hearing and subjected to routine physical and laboratory examinations. Patients who had a history of epilepsy or seizure; a significant or unstable neurologic disorder; a cardiac pacemaker; previous brain injury or surgery; any metal clips, plates, or other metal items in the head; or substance dependency were excluded. Patients were randomly assigned to the active and sham groups using software (ratio of active to sham was 2:1). The active group (N = 78) and the sham group (N = 39) respectively received either active rTMS or the placebo-controlled sham rTMS. For an overview of the clinical trial design, see Fig. 1. The groups did not differ with respect to demographic and clinical characteristics (Table 1). All participants provided written informed consent, and the protocol was approved by the ethics committee of Beijing Anding Hospital. 2.2. rTMS procedure A randomized, double-blind parallel group design was used with a sham stimulation control condition. For both groups, rTMS was administered with a CADWELL 9-cm circular coil at 10 Hz for 4 s at 80% motor threshold (MT), with an inter-train interval of 56 s, 40 trains per minute, 20 min each day (800 pulses per day) to the left DLPFC. The coil was parallel to the scalp of the skull, with the handle pointing backward in the active rTMS condition. As per previous studies, the site of stimulation was defined by a point 5 cm anterior to the point where maximum stimulation of the abductor pollicis brevis muscle was observed. The sham stimulation was delivered using the same rTMS parameters as active stimulation, and the coil was angled 90 degree off the head so that there was stimulation of scalp muscles and associated acoustic artifact, but presumably no current induction within the cortex. Patients received two rTMS treatment courses consisting of 10 daily sessions during a 2-week period, with a 2-week period of no treatment between each course.
2. Materials and methods 2.1. Subjects A total of 117 inpatients and outpatients with schizophrenia were recruited from Peking University Sixth Hospital and Beijing
Fig. 1. Treatment study flowchart.
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Table 1 Demographic and clinical variables of the two groups. Characteristics Sex (male:female) Mean age (SD), year Mean (SD) length of illness, year Mean education years (SD), year Medication treatment Atypical Typical Atypical and Typical % in Clozapine Dose of chlorpromazine equivalents Clinical comorbidities BMI index Mean (SD) PANSS score Positive score Negative score General score Total score
Active rTMS (n = 78)
Sham rTMS (n = 39)
P value 0.158b 1.000a 0.239a 0.797a 0.073b
44:34 46.87 ± 7.87 20.53 ± 10.97 10.28 ± 2.58
28:11 46.87 ± 9.07 17.97 ± 11.03 10.15 ± 2.47
39 18 21 37.18% 411.78 ± 194.19 35 25.02 ± 4.47
28 6 5 28.21% 438.46 ± 189.58 13 25.18 ± 3.14
0.335b 0.482a 0.232b 0.819a
12.41 ± 5.40 26.19 ± 3.59 30.30 ± 6.50 69.38 ± 11.64
12.38 ± 5.66 26.97 ± 4.37 29.82 ± 4.87 69.18 ± 10.99
0.981a 0.337a 0.416a 0.927a
PANSS: positive and negative syndrome scale. a Independent samples t test. b Chi-squared tests.
Patients’ current antipsychotic treatments were unchanged during the rTMS study. All treatments were performed by a psychiatrist trained in rTMS administration, who did not inform patients of their treatment group or participate in the evaluation of study results. 2.3. Assessments Four blinded investigators performed assessments. The primary outcome parameters were changes in negative symptoms as assessed with PANSS and SANS. The intraclass correlation coefficient (ICC) was 0.91 between investigators for PANSS [12]. Secondary outcome parameters were the Udvalg for Kliniske Under sogelser (UKU) Side Effect Rating Scale and the CGI severity of illness (CGI-S) and global improvement (CGI-I) scales. Clinical assessments occurred at baseline and 2-week intervals during treatment through the end of the 6-week treatment. In addition, routine blood, biochemical, ECG, and EEG examinations were given at baseline and at the end of treatment. We conducted three followup sessions at 4, 12, and 24 weeks after the last treatment at which we assessed the PANSS, SANS, and CGI. 2.4. Data analysis The possibility of baseline differences in demographic and clinical variables was investigated with t-tests and chi-squared tests. Repeated measures analysis of variance (ANOVA) were performed on the primary outcome variables (PANSS, SANS, and CGI), with group (active vs. sham) as the between subject factor and time (baseline, 2weeks, 6 weeks) as the within subject factor. Repeated measures analysis of covariance was used to compare scale scores at follow-up. For the CGI-I, only the post-treatment values were compared, as it was not possible to rate this parameter at the onset of the study. Data are presented as mean (with standard deviation) and were analyzed using SPSS 16.0.
biochemistry tests. In addition, no adverse events were observed, as assessed by the UKU Side Effect Rating Scale except for mild headache. Only three patients in the active group and one patient in the sham group reported a headache, which lasted 2–3 days, and no abnormalities were observed during follow up. All other patients tolerated the rTMS stimulation well and did not report any adverse effects. For the primary outcome measure of PANSS (Table 2), repeated measures ANOVA revealed a significant group-by-time interaction for PANSS negative score (P < 0.05) and PANSS total score (P < 0.05). No group-by-time interaction was found for the PANSS positive score and general score. Further, simple effect analysis showed that there were no significant differences between the two groups for any PANSS scales after the 2-week treatment. However, a significant reduction was observed for the PANSS negative score [t (115) = −2.467, P < 0.05] within the active group compared to the sham group after the 6-week treatment. There were also improvements in the SANS negative symptom scores (Table 2). Repeated measures ANOVA revealed a significant group-by-time interaction for volition abulia (P < 0.05), interest-social lack (P < 0.01) and SANS total scores (P < 0.01). No group-by-time interaction was found for the other domains of SANS. Further, simple effect analysis showed no significant differences between the two groups for any SANS scales after the 2-week treatment. However, significant improvements were observed for volition abulia [t (115) = −2.086, P < 0.05] and SANS total scores [t (115) = −2.141, P < 0.05] within the active group compared to the sham group after the 6-week treatment. By contrast, no differences in the group-by-time interaction for CGI-I (P = 0.400) and CGI-S (P = 0.132) were found after removing extreme values (leaving 76 and 37 patients in the active and sham group, respectively) (Table 2). In addition, after the 6-week treatment, there were significant differences between the active and sham groups for CGI-I and CGI-S.
3. Results
3.2. Follow-up of the active group
3.1. Comparison of the changes in clinical status between the active and sham rTMS groups
We conducted a 24-week follow-up assessment of active rTMS group using the PANSS, SANS, and CGI scales to evaluate the continuous effect of rTMS on the improvement of negative symptoms at 4, 12, and 24 weeks after the last treatment. In total, 69 patients completed the first follow-up, 68 patients completed the second follow-up and 56 patients completed the third follow-up.
All patients completed the treatment protocol. We did not observe any adverse effects of rTMS assessed by physical examination, neurologic examination, ECG, or routine blood and blood
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Table 2 Mean PANSS, SANS and CGI, including their particular symptom dimensions at baseline and after 2-week, 6-week of treatments. Scale
PANSS Positive Negative General Total score SANS Affective Flattening/Blunting Poverty of thought Volition bulia Interest-social lack Attention dysfunction Total scores CGIa Severity of Illness Global Improvement
Active rTMS (n = 78)
Time × group
Sham rTMS (n = 39)
Baseline
Week 2
Week 6
Baseline
Week 2
Week 6
F
P
12.41 (5.40) 26.19 (3.59) 30.78 (6.50) 69.38 (11.64)
11.32 (5.14) 22.87 (4.26) 26.91 (4.99) 61.10 (11.14)
10.85 (4.78) 20.03* (5.04) 24.40 (4.67) 55.27 (11.74)
12.38 (5.66) 26.97 (4.37) 29.82 (4.87) 69.18 (10.99)
10.54 (4.45) 23.51 (5.56) 26.74 (4.89) 60.79 (12.09)
11.13 (4.72) 22.59 (5.79) 25.87 (5.53) 59.59 (12.83)
0.895
0.411
3.177
0.044
2.073
0.131
3.140
0.045
20.92 (3.42) 11.64 (3.52) 10.74 (1.98) 13.85 (2.40) 6.46 (2.33) 63.62 (9.93)
18.92 (3.43) 10.50 (3.70) 9.59 (2.04) 12.05 (2.75) 5.49 (2.20) 56.55 (11.03)
16.63 (4.49) 8.77 (3.73) 8.53* (2.13) 10.59 (3.08) 4.64 (2.26) 49.15* (12.79)
21.59 (3.67) 12.03 (4.26) 10.82 (2.57) 13.13 (2.77) 6.46 (3.10) 64.03 (13.53)
19.56 (3.96) 10.87 (4.05) 9.67 (2.74) 12.46 (2.70) 5.31 (3.23) 57.87 (13.80)
18.51 (4.29) 9.85 (4.59) 9.49 (2.74) 11.74 (2.84) 5.26 (3.46) 54.85 (14.99)
1.982
0.142
0.789
0.456
3.301
0.039
5.718
0.004
2.390
0.096
4.135
0.017
4.95 (0.86)
4.22 (0.86) 3.14 (0.71)
3.74 (0.79) 2.83 (0.86)
5.05 (0.88)
4.43 (0.77) 3.38 (0.68)
4.16 (0.69) 3.19 (0.85)
2.047
0.132
0.713
0.400
Active means the real rTMS treatment group, Sham means the sham rTMS treatment group. * P < 0.05, compared with sham group. a After removing the extreme values of CGI-S and CGI-I, left 76 patients of active group and 37 patients of sham group.
Repeated measures analysis of covariance, with age, education, illness duration, and dose of chlorpromazine equivalents as the covariates, revealed that the changes of PANSS, SANS, and CGI score in the active group were not statistically significant over the course of follow-up (all P > 0.05; Fig. 2), indicating sustained therapeutic effects of rTMS. 4. Discussion In this double-blind, randomized, sham-controlled trial of left DLPFC high-frequency rTMS, we found a significant therapeutic benefit of 6 weeks of active rTMS in alleviating the negative symptoms of schizophrenia (as measured by PANSS and SANS), but no effect on the CGI. The 2-week treatment was however insufficient to elicit any clinical benefit. As the effect was still observed at 24 weeks of follow up, we conclude that high-frequency rTMS over 6 weeks is a feasible and safe treatment for negative symptoms, but
has no effect on positive symptoms. Our results are consistent with at least two previous studies [6,22]. However, two other parallelgroup randomized studies showed no effect on negative symptoms [9,20]. We report that the effects of rTMS persisted through 24 weeks of follow-up, in accordance with a previous study with a 1-month follow-up [25]. However, a separate study reported that the beneficial effect of high-frequency rTMS on negative symptoms was inconsistent or transient [19]. Taken together, the different outcomes might be, at least, due to considerable methodological differences among the studies including sample sizes or patientdependent variables, as well as the stimulation paradigms and the definitions of outcome criteria (positive or negative symptoms). In addition, one prior study reported no positive effects of rTMS on CGI-S in their over-all sample, but reported a moderate effect of rTMS on CGI-S in a subgroup of patients with more pronounced negative symptoms [5]. Our result also showed no
Fig. 2. PANSS, SANS and CGI analysis at baseline, the end of treatment and the three times of follow-up for real group, **P < 0.01, compared with the end of treatment and the three times of follow-up.
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significant improvement in general clinical states in this study. Perhaps, a modest effect on CGI may be masked by the unspecific/placebo effects of the rTMS procedure in studies with small samples sizes [9,16]. Additionally, Rabinowitz revealed that PANSS and CGI-S are correlated but are not synonymous [23]. We thus speculate that CGI may be less sensitive than PANSS and SANS in measuring the negative symptoms of schizophrenia. Potential mechanisms underlying the effects of rTMS remain to be established. However, a number of studies in humans and animal models suggest that rTMS induces dopamine release in mesolimbic and mesostriatal structures [13,14,18,26]. Thus, release of endogenous dopamine in subcortical structures seems the most likely mechanism of action [3]. The present study has several limitations. First, we did not perform a comprehensive comparison of different stimulation parameters on clinical outcome, which would be difficult due to practical limitations. Second, we did not compare potentially different effects of rTMS in inpatients versus outpatients. Third, we did not conduct a 24-week follow-up assessment of the sham rTMS group. In summary, we found a continuous beneficial effect of 10 Hz rTMS treatment on PANSS, SANS and CGI in schizophrenia patients with predominant negative symptoms in the largest sample population yet studied to our knowledge. In conclusion, high-frequency 10-Hz rTMS stimulation over the left DLPFC at a high stimulation intensity with a sufficient number of applied stimulating pulses may augment the effects of antipsychotics in alleviating majority of the negative symptoms in patients with schizophrenia.
[6]
[7]
[8]
[9]
[10]
[11]
[12] [13]
[14]
[15] [16]
Disclosure statement There are no conflicts of interest to report. Role of the funding source
[17]
[18]
This study was partially supported by Beijing Municipal Science & Technology Commission grant (No. 0906001040291). [19]
Acknowledgements The authors are grateful to Zhan jiang Li, Yan ping Ren for their technical and statistical assistance. Appreciation is also owed to the patients, clinical psychiatrists, and nursing staff in Peking University Sixth Hospital and Beijing Anding Hospital for their participation and collaboration. The authors also thank the anonymous reviewers for their helpful comments.
[20]
[21]
[22]
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The effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) on negative symptoms of schizophrenia and the follow-up study Wen Xiang Quan a,b,1 , Xiao Lin Zhu c,1 , Hong Qiao a,b , Wu Fang Zhang a,b , Shu Ping Tan c , Dong Feng Zhou a,b , Xiang Qun Wang a,b,∗ a
Institute of Mental Health, Peking University, 51 Hua Yuan Bei Road, Beijing 100191, China Key Laboratory of Mental Health, Ministry of Health, Institute of Mental Health, The Sixth Hospital, Peking University, China c Center for Psychiatric Research, Beijing Huilongguan Hospital, Beijing 100096, China b
h i g h l i g h t s • 6-week rTMS significantly improved the negative symptoms of schizophrenia. • CGI severity of illness scale was not improved by rTMS in schizophrenia. • The improvement of negative symptoms in schizophrenia was maintained for 24 weeks.
a r t i c l e
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Article history: Received 9 July 2014 Received in revised form 25 September 2014 Accepted 16 October 2014 Available online 24 October 2014 Keywords: Repetitive transcranial magnetic stimulation Schizophrenia Negative symptoms
a b s t r a c t In this double-blind, randomized controlled study, we assessed the therapeutic effects of high-frequency left dorsolateral prefrontal cortex (DLPFC) repetitive transcranial magnetic stimulation (rTMS) on negative symptoms of schizophrenia. For the study, 117 patients with prominent negative symptoms were randomized to a 20-day course of either active rTMS applied to the left DLPFC (n = 78) or sham rTMS (n = 39). The primary outcome measures were the Positive and Negative Symptom Scale (PANSS) and the Scale for the Assessment of Negative Symptoms (SANS). Secondary outcomes included the Clinical Global Impressions Scale (CGI) and the Udvalg for Kliniske Under sogelser (UKU) Side Effect Rating Scale. We found that treatment with high-frequency rTMS for 6weeks significantly improved negative symptoms in the active group as compared to the sham group. However, active rTMS was not correlated with significant improvement in the CGI severity of illness scale (CGI-S). The improvement of negative symptoms persisted to the 24-week follow-up assessment. These results indicate that there is a lasting beneficial effect of rTMS on negative symptoms in absence of decrease in CGI scores. We conclude that rTMS may serve as a relatively noninvasive treatment that alleviates negative symptoms in patients with schizophrenia. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction The core symptoms of schizophrenia can be divided into negative and positive symptoms. Positive symptoms include abnormal emotions and behavior, such as delusions, disorganized thoughts and actions, and hallucinations. In contrast, negative symptoms are defined as an absence of normal emotions and behaviors, including apathy, loss of interest in everyday activities,
∗ Corresponding author at: Institute of Mental Health, Peking University, 51 Hua Yuan Bei Road, Beijing 100191, China. Tel.: +86 10 82802835; fax: +86 10 62026310. E-mail address: [email protected] (X.Q. Wang). 1 Quan WX and Zhu XL contributed to this work equally. http://dx.doi.org/10.1016/j.neulet.2014.10.029 0304-3940/© 2014 Elsevier Ireland Ltd. All rights reserved.
and feelings of social isolation. Negative symptoms contribute substantially to the prolonged course and mental disability associated with schizophrenia. While negative symptoms can be attenuated by atypical antipsychotics, the benefit is clinically unsatisfactory. Therefore, developing a more effective therapy for negative symptoms is critical for improving schizophrenia treatment. Studies have consistently suggested that prefrontal dysfunction, particularly in the dorsolateral prefrontal cortex (DLPFC), is involved in the pathophysiology of negative symptoms of schizophrenia [7,21,27]. Further, indices of negative symptoms have been shown to negatively correlate with blood flow to the frontal cerebrum [24] and prefrontal perfusion [17]. Structural impairments of the prefrontal cortex in schizophrenia have also
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been associated with negative symptoms and this may be a corollary of dopamine hypoactivation [15]. Repetitive transcranial magnetic stimulation (rTMS) is a neurophysiological technique introduced by Barker in 1985 [2] that permits noninvasive electromagnetic neurostimulationin specific areas of cerebral cortex. Animal and human studies have shown that rTMS modulates neuronal activity of cortical brain areas and relevant neuronal circuits, while also affecting the regulation of serotonin receptors and the release of dopamine in the mesolimbic and mesostriatal pathways [11,14,26]. Thus, rTMS represents an attractive potential therapy for schizophrenia; however, reports on the efficacy of rTMS in treating the disease are conflicting. The most important factors that influence rTMS experimental results are the stimulation parameters (e.g., the number of stimulating pulses administered, the total number of stimulation sessions, the stimulation site, the conditions for blinding, etc.). Therefore, different rTMS protocols may explain these contradictory findings, highlighting the importance of optimizing rTMS parameters. It has been demonstrated repeatedly that high-frequency rTMS (5–25 Hz) applied over the left prefrontal cortex (PFC) increases brain excitability, whereas low-frequency rTMS (1 Hz and low) has the opposite effect [8]. The first report on rTMS effects on negative symptoms was an open study targeting the prefrontal cortex of six patients with 10 days of 20 Hz rTMS at 80% MT [4] that described a general reduction of the negative symptoms subscale of the Positive and Negative Symptom Scale (PANSS). Two follow-up studies also reported improvement of negative symptoms [10,25]. However, the results of subsequent parallel design, randomized, double-blind, controlled studies with a longer testing period and larger subject group have been contradictory despite several methodological improvements (e.g., parallel design and a higher number of pulses) [6,9,11,16,20,22]. High-frequency rTMS to the left DLPFC did not alleviate negative symptoms in two studies with samples of 22 [9] and 16 [20] for chronic schizophrenia patients. In contrast, Hajak and Jin were able to show a significant improvement in total PANSS negative symptoms over time when compared to sham rTMS using a higher dosage and bilateral frontal cortex as a treatment site [6,11]. The intensity of rTMS was also higher in this study (110% vs. 90% MT) and included patients with schizoaffective disorder, who respond better to rTMS than schizophrenia patients. Prikryl reported similar results using the same parameters and an extended treatment time (3 weeks vs. 2 weeks) [22]. The discrepancies between studies may be due to different experimental paradigms, stimuli, and sample sizes. As result, no definitive conclusions regarding the treatment potential of rTMS can presently be made, and it remains necessary to demonstrate symptom reductions are sustained. Moreover, the clinical significance (i.e., degree of functional improvement) of these effects is largely unknown. In the present study, we aimed to investigate the efficacy of high-frequency rTMS on negative symptoms and general clinical state assessed by PANSS, Scale for the Assessment of Negative Symptoms (SANS), and Clinical Global Impression (CGI) scale in a relatively large and well-characterized sample of patients with schizophrenia through a randomized, double-blind, and sham-controlled trial. We hypothesized that negative symptoms and the general clinical state would be significantly improved in patients with schizophrenia following the application of high-frequency rTMS to the left dorsolateral prefrontal cortex (DLPFC).
Anding Hospital between January 2007 and June 2010. Individuals who meet DSM-IV diagnosis for schizophrenia [1] and had a PANSS negative symptom score ≥ 20 were enrolled. All diagnoses were made by a single psychiatrist and then confirmed by a senior psychiatrist. Patients were included only if they were stabilized for at least 3 months by a consistent regimen of antipsychotics. The age of enrollees ranged from 20 to 60 years. All patients were screened for normal hearing and subjected to routine physical and laboratory examinations. Patients who had a history of epilepsy or seizure; a significant or unstable neurologic disorder; a cardiac pacemaker; previous brain injury or surgery; any metal clips, plates, or other metal items in the head; or substance dependency were excluded. Patients were randomly assigned to the active and sham groups using software (ratio of active to sham was 2:1). The active group (N = 78) and the sham group (N = 39) respectively received either active rTMS or the placebo-controlled sham rTMS. For an overview of the clinical trial design, see Fig. 1. The groups did not differ with respect to demographic and clinical characteristics (Table 1). All participants provided written informed consent, and the protocol was approved by the ethics committee of Beijing Anding Hospital. 2.2. rTMS procedure A randomized, double-blind parallel group design was used with a sham stimulation control condition. For both groups, rTMS was administered with a CADWELL 9-cm circular coil at 10 Hz for 4 s at 80% motor threshold (MT), with an inter-train interval of 56 s, 40 trains per minute, 20 min each day (800 pulses per day) to the left DLPFC. The coil was parallel to the scalp of the skull, with the handle pointing backward in the active rTMS condition. As per previous studies, the site of stimulation was defined by a point 5 cm anterior to the point where maximum stimulation of the abductor pollicis brevis muscle was observed. The sham stimulation was delivered using the same rTMS parameters as active stimulation, and the coil was angled 90 degree off the head so that there was stimulation of scalp muscles and associated acoustic artifact, but presumably no current induction within the cortex. Patients received two rTMS treatment courses consisting of 10 daily sessions during a 2-week period, with a 2-week period of no treatment between each course.
2. Materials and methods 2.1. Subjects A total of 117 inpatients and outpatients with schizophrenia were recruited from Peking University Sixth Hospital and Beijing
Fig. 1. Treatment study flowchart.
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Table 1 Demographic and clinical variables of the two groups. Characteristics Sex (male:female) Mean age (SD), year Mean (SD) length of illness, year Mean education years (SD), year Medication treatment Atypical Typical Atypical and Typical % in Clozapine Dose of chlorpromazine equivalents Clinical comorbidities BMI index Mean (SD) PANSS score Positive score Negative score General score Total score
Active rTMS (n = 78)
Sham rTMS (n = 39)
P value 0.158b 1.000a 0.239a 0.797a 0.073b
44:34 46.87 ± 7.87 20.53 ± 10.97 10.28 ± 2.58
28:11 46.87 ± 9.07 17.97 ± 11.03 10.15 ± 2.47
39 18 21 37.18% 411.78 ± 194.19 35 25.02 ± 4.47
28 6 5 28.21% 438.46 ± 189.58 13 25.18 ± 3.14
0.335b 0.482a 0.232b 0.819a
12.41 ± 5.40 26.19 ± 3.59 30.30 ± 6.50 69.38 ± 11.64
12.38 ± 5.66 26.97 ± 4.37 29.82 ± 4.87 69.18 ± 10.99
0.981a 0.337a 0.416a 0.927a
PANSS: positive and negative syndrome scale. a Independent samples t test. b Chi-squared tests.
Patients’ current antipsychotic treatments were unchanged during the rTMS study. All treatments were performed by a psychiatrist trained in rTMS administration, who did not inform patients of their treatment group or participate in the evaluation of study results. 2.3. Assessments Four blinded investigators performed assessments. The primary outcome parameters were changes in negative symptoms as assessed with PANSS and SANS. The intraclass correlation coefficient (ICC) was 0.91 between investigators for PANSS [12]. Secondary outcome parameters were the Udvalg for Kliniske Under sogelser (UKU) Side Effect Rating Scale and the CGI severity of illness (CGI-S) and global improvement (CGI-I) scales. Clinical assessments occurred at baseline and 2-week intervals during treatment through the end of the 6-week treatment. In addition, routine blood, biochemical, ECG, and EEG examinations were given at baseline and at the end of treatment. We conducted three followup sessions at 4, 12, and 24 weeks after the last treatment at which we assessed the PANSS, SANS, and CGI. 2.4. Data analysis The possibility of baseline differences in demographic and clinical variables was investigated with t-tests and chi-squared tests. Repeated measures analysis of variance (ANOVA) were performed on the primary outcome variables (PANSS, SANS, and CGI), with group (active vs. sham) as the between subject factor and time (baseline, 2weeks, 6 weeks) as the within subject factor. Repeated measures analysis of covariance was used to compare scale scores at follow-up. For the CGI-I, only the post-treatment values were compared, as it was not possible to rate this parameter at the onset of the study. Data are presented as mean (with standard deviation) and were analyzed using SPSS 16.0.
biochemistry tests. In addition, no adverse events were observed, as assessed by the UKU Side Effect Rating Scale except for mild headache. Only three patients in the active group and one patient in the sham group reported a headache, which lasted 2–3 days, and no abnormalities were observed during follow up. All other patients tolerated the rTMS stimulation well and did not report any adverse effects. For the primary outcome measure of PANSS (Table 2), repeated measures ANOVA revealed a significant group-by-time interaction for PANSS negative score (P < 0.05) and PANSS total score (P < 0.05). No group-by-time interaction was found for the PANSS positive score and general score. Further, simple effect analysis showed that there were no significant differences between the two groups for any PANSS scales after the 2-week treatment. However, a significant reduction was observed for the PANSS negative score [t (115) = −2.467, P < 0.05] within the active group compared to the sham group after the 6-week treatment. There were also improvements in the SANS negative symptom scores (Table 2). Repeated measures ANOVA revealed a significant group-by-time interaction for volition abulia (P < 0.05), interest-social lack (P < 0.01) and SANS total scores (P < 0.01). No group-by-time interaction was found for the other domains of SANS. Further, simple effect analysis showed no significant differences between the two groups for any SANS scales after the 2-week treatment. However, significant improvements were observed for volition abulia [t (115) = −2.086, P < 0.05] and SANS total scores [t (115) = −2.141, P < 0.05] within the active group compared to the sham group after the 6-week treatment. By contrast, no differences in the group-by-time interaction for CGI-I (P = 0.400) and CGI-S (P = 0.132) were found after removing extreme values (leaving 76 and 37 patients in the active and sham group, respectively) (Table 2). In addition, after the 6-week treatment, there were significant differences between the active and sham groups for CGI-I and CGI-S.
3. Results
3.2. Follow-up of the active group
3.1. Comparison of the changes in clinical status between the active and sham rTMS groups
We conducted a 24-week follow-up assessment of active rTMS group using the PANSS, SANS, and CGI scales to evaluate the continuous effect of rTMS on the improvement of negative symptoms at 4, 12, and 24 weeks after the last treatment. In total, 69 patients completed the first follow-up, 68 patients completed the second follow-up and 56 patients completed the third follow-up.
All patients completed the treatment protocol. We did not observe any adverse effects of rTMS assessed by physical examination, neurologic examination, ECG, or routine blood and blood
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Table 2 Mean PANSS, SANS and CGI, including their particular symptom dimensions at baseline and after 2-week, 6-week of treatments. Scale
PANSS Positive Negative General Total score SANS Affective Flattening/Blunting Poverty of thought Volition bulia Interest-social lack Attention dysfunction Total scores CGIa Severity of Illness Global Improvement
Active rTMS (n = 78)
Time × group
Sham rTMS (n = 39)
Baseline
Week 2
Week 6
Baseline
Week 2
Week 6
F
P
12.41 (5.40) 26.19 (3.59) 30.78 (6.50) 69.38 (11.64)
11.32 (5.14) 22.87 (4.26) 26.91 (4.99) 61.10 (11.14)
10.85 (4.78) 20.03* (5.04) 24.40 (4.67) 55.27 (11.74)
12.38 (5.66) 26.97 (4.37) 29.82 (4.87) 69.18 (10.99)
10.54 (4.45) 23.51 (5.56) 26.74 (4.89) 60.79 (12.09)
11.13 (4.72) 22.59 (5.79) 25.87 (5.53) 59.59 (12.83)
0.895
0.411
3.177
0.044
2.073
0.131
3.140
0.045
20.92 (3.42) 11.64 (3.52) 10.74 (1.98) 13.85 (2.40) 6.46 (2.33) 63.62 (9.93)
18.92 (3.43) 10.50 (3.70) 9.59 (2.04) 12.05 (2.75) 5.49 (2.20) 56.55 (11.03)
16.63 (4.49) 8.77 (3.73) 8.53* (2.13) 10.59 (3.08) 4.64 (2.26) 49.15* (12.79)
21.59 (3.67) 12.03 (4.26) 10.82 (2.57) 13.13 (2.77) 6.46 (3.10) 64.03 (13.53)
19.56 (3.96) 10.87 (4.05) 9.67 (2.74) 12.46 (2.70) 5.31 (3.23) 57.87 (13.80)
18.51 (4.29) 9.85 (4.59) 9.49 (2.74) 11.74 (2.84) 5.26 (3.46) 54.85 (14.99)
1.982
0.142
0.789
0.456
3.301
0.039
5.718
0.004
2.390
0.096
4.135
0.017
4.95 (0.86)
4.22 (0.86) 3.14 (0.71)
3.74 (0.79) 2.83 (0.86)
5.05 (0.88)
4.43 (0.77) 3.38 (0.68)
4.16 (0.69) 3.19 (0.85)
2.047
0.132
0.713
0.400
Active means the real rTMS treatment group, Sham means the sham rTMS treatment group. * P < 0.05, compared with sham group. a After removing the extreme values of CGI-S and CGI-I, left 76 patients of active group and 37 patients of sham group.
Repeated measures analysis of covariance, with age, education, illness duration, and dose of chlorpromazine equivalents as the covariates, revealed that the changes of PANSS, SANS, and CGI score in the active group were not statistically significant over the course of follow-up (all P > 0.05; Fig. 2), indicating sustained therapeutic effects of rTMS. 4. Discussion In this double-blind, randomized, sham-controlled trial of left DLPFC high-frequency rTMS, we found a significant therapeutic benefit of 6 weeks of active rTMS in alleviating the negative symptoms of schizophrenia (as measured by PANSS and SANS), but no effect on the CGI. The 2-week treatment was however insufficient to elicit any clinical benefit. As the effect was still observed at 24 weeks of follow up, we conclude that high-frequency rTMS over 6 weeks is a feasible and safe treatment for negative symptoms, but
has no effect on positive symptoms. Our results are consistent with at least two previous studies [6,22]. However, two other parallelgroup randomized studies showed no effect on negative symptoms [9,20]. We report that the effects of rTMS persisted through 24 weeks of follow-up, in accordance with a previous study with a 1-month follow-up [25]. However, a separate study reported that the beneficial effect of high-frequency rTMS on negative symptoms was inconsistent or transient [19]. Taken together, the different outcomes might be, at least, due to considerable methodological differences among the studies including sample sizes or patientdependent variables, as well as the stimulation paradigms and the definitions of outcome criteria (positive or negative symptoms). In addition, one prior study reported no positive effects of rTMS on CGI-S in their over-all sample, but reported a moderate effect of rTMS on CGI-S in a subgroup of patients with more pronounced negative symptoms [5]. Our result also showed no
Fig. 2. PANSS, SANS and CGI analysis at baseline, the end of treatment and the three times of follow-up for real group, **P < 0.01, compared with the end of treatment and the three times of follow-up.
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significant improvement in general clinical states in this study. Perhaps, a modest effect on CGI may be masked by the unspecific/placebo effects of the rTMS procedure in studies with small samples sizes [9,16]. Additionally, Rabinowitz revealed that PANSS and CGI-S are correlated but are not synonymous [23]. We thus speculate that CGI may be less sensitive than PANSS and SANS in measuring the negative symptoms of schizophrenia. Potential mechanisms underlying the effects of rTMS remain to be established. However, a number of studies in humans and animal models suggest that rTMS induces dopamine release in mesolimbic and mesostriatal structures [13,14,18,26]. Thus, release of endogenous dopamine in subcortical structures seems the most likely mechanism of action [3]. The present study has several limitations. First, we did not perform a comprehensive comparison of different stimulation parameters on clinical outcome, which would be difficult due to practical limitations. Second, we did not compare potentially different effects of rTMS in inpatients versus outpatients. Third, we did not conduct a 24-week follow-up assessment of the sham rTMS group. In summary, we found a continuous beneficial effect of 10 Hz rTMS treatment on PANSS, SANS and CGI in schizophrenia patients with predominant negative symptoms in the largest sample population yet studied to our knowledge. In conclusion, high-frequency 10-Hz rTMS stimulation over the left DLPFC at a high stimulation intensity with a sufficient number of applied stimulating pulses may augment the effects of antipsychotics in alleviating majority of the negative symptoms in patients with schizophrenia.
[6]
[7]
[8]
[9]
[10]
[11]
[12] [13]
[14]
[15] [16]
Disclosure statement There are no conflicts of interest to report. Role of the funding source
[17]
[18]
This study was partially supported by Beijing Municipal Science & Technology Commission grant (No. 0906001040291). [19]
Acknowledgements The authors are grateful to Zhan jiang Li, Yan ping Ren for their technical and statistical assistance. Appreciation is also owed to the patients, clinical psychiatrists, and nursing staff in Peking University Sixth Hospital and Beijing Anding Hospital for their participation and collaboration. The authors also thank the anonymous reviewers for their helpful comments.
[20]
[21]
[22]
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